Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is a growing body of evidence that sensory neuropathy in diabetes is associated with abnormal calcium signaling in dorsal root ganglion (DRG) neurons. Enhanced influx of calcium via multiple high-threshold calcium currents is present in sensory neurons of several models of diabetes mellitus, including the spontaneously diabetic BioBred/Worchester (BB/W) rat and the chemical streptozotocin (STZ)-induced rat. We believe that abnormal calcium signaling in diabetes has pathologic significance as elevation of calcium influx and cytosolic calcium release has been implicated in other neurodegenerative conditions characterized by neuronal dysfunction and death. Using electrophysiologic and pharmacologic techniques, the present study provides evidence that significant impairment of G-protein-coupled modulation of calcium channel function may underlie the enhanced calcium entry in diabetes. N- and P-type voltage-activated, high-threshold calcium channels in DRGs are coupled to mu opiate receptors via inhibitory G(o)-type G proteins. The responsiveness of this receptor coupled model was tested in dorsal root ganglion (DRG) neurons from spontaneously-diabetic BB/W rats, and streptozotocin-induced (STZ) diabetic rats. Intracellular dialysis with GTPgammaS decreased calcium current amplitude in diabetic BB/W DRG neurons compared with those of age-matched, nondiabetic controls, suggesting that inhibitory G-protein activity was diminished in diabetes, resulting in larger calcium currents. Facilitation of calcium current density (I(DCa)) by large-amplitude depolarizing prepulses (proposed to transiently inactivate G proteins), was significantly less effective in neurons from BB/W and STZ-induced diabetic DRGs. Facilitation was enhanced by intracellular dialysis with GTPgammaS, decreased by pertussis toxin, and abolished by GDPbetaS within 5 min. Direct measurement of GTPase activity using opiate-mediated GTPgamma[(35)S] binding, confirmed that G-protein activity was significantly diminished in STZ-induced diabetic neurons compared with age-matched nondiabetic controls. Diabetes did not alter the level of expression of mu opiate receptors and G-protein alpha subunits. These studies indicate that impaired regulation of calcium channels by G proteins is an important mechanism contributing to enhanced calcium influx in diabetes.
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PMID:Impaired inhibitory G-protein function contributes to increased calcium currents in rats with diabetic neuropathy. 1149 48

Several authors have reported higher skin temperature in the feet of diabetic subjects with autonomic neuropathy. We reexamined this association in a cross-sectional study of 712 veterans with diabetes mellitus. Potential subjects included all diabetic patients enrolled in a general internal medicine clinic at a veterans affairs healthcare system. Sensory neuropathy was defined as any pedal insensitivity to the 5.07 monofilament. Autonomic neuropathy was determined using standard cardiovascular reflex tests. An infrared surface scanner was used to measure foot skin temperature at multiple sites. Subjects with sensory neuropathy had lower mean plantar foot skin temperature than those without (28.4 degrees C vs. 28.9 degrees C, P=.0101). Autonomic neuropathy as a dichotomous variable was unrelated to foot skin temperature. Foot skin temperature, though, negatively correlated with greater drop in systolic blood pressure with standing, which is an indicator of autonomic neuropathy (r=-.08, P=.0385). Adjustment for potential confounding factors using multiple linear regression analysis resulted in diminution of the associations between foot skin temperature and sensory neuropathy or orthostatic blood pressure drop, but the latter association remained statistically significant in the right foot. Diabetic veterans with sensory or autonomic neuropathy do not have higher foot skin temperature. Our results suggest that skin temperature may be slightly lower with higher orthostatic blood pressure fall. Other causes exist for the frequently observed differences in skin temperature in the feet of diabetic subjects.
J Diabetes Complications
PMID:Skin temperature in the neuropathic diabetic foot. 1152 1

Among diabetics, peripheral neuropathy is common and ultimately accounts for significant morbidity. The ultimate consequence of such sensory defects involving the lower extremities may be foot ulceration initiated by trauma that is inapparent to the patient. Such ulcerations often lead to lower extremity amputation, a complication that is 15 times higher in diabetic versus non-diabetic patients. Preliminary clinical studies have demonstrated improvement in signs and symptoms of sensory neuropathy in patients with lower extremity vascular occlusive disease following intramuscular injection of naked DNA encoding vascular endothelial growth factor (VEGF). To determine if such a strategy could be applied to diabetic patients, including those without evidence of large vessel occlusive disease, we investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. In two different animal models of diabetics, nerve blood flow and the number of vasa nervorum were found to be markedly attenuated resulting in severe peripheral neuropathy. In contrast, following VEGF gene transfer, vascularity and blood flow in nerves of treated animals were similar to those of non-diabetic controls; constitutive overexpression of VEGF resulted in restoration of large and small fiber peripheral nerve function. These findings implicate microvascular disruption as the basis for diabetic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment strategy for this pernicious disorder. Accordingly, we now seek to address the following two objectives: 1. Objective #1: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes and associated macrovascular disease involving the lower extremities. 2. Objective #2: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes without macrovascular disease involving the lower extremities. The protocol outlined in this Investigational New Drug Application has been designed as a Phase I/II, single-site, dose escalating, double-blind, placebo controlled study to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes with or without macrovascular disease involving the lower extremities. Diabetic males or females > 21 years old with sensory neuropathy with or without macrovascular disease will be eligible. A total of 192 patients will be recruited into two arms of the study (each arm consisting of 96 patients) over a period of 4 years (the fifth year will be limited to follow-up examinations). The 96 patients in each of the two arms of the study will comprise 3 cohorts, each consisting of 32 patients. Within each of these cohorts, patients will be randomized to receive phVEGF165 or placebo based upon a 3:1 randomization ratio. Thus, at the completion of the study, 24 patients will have each received a given dose (1, 2, or 4 mg phVEGF165) and 24 patients will have received placebo. Doses will be employed in a serial dose-escalating fashion. The entire volume of the study drug will be divided and delivered in 8 intramuscular injections administered into the foot, calf muscle, or distal thigh muscle of the affected extremity. Following the initial set of injections, repeat treatment with an identical dose will be provided 2 and 4 weeks after initial treatment.
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PMID:VEGF gene transfer for diabetic neuropathy. 1152 48

Increased pressure due, to sensory neuropathy, is important in the development of plantar ulceration in type II diabetes. However, additional factors are thought to pre-dispose the skin tissue to ulceration. Autonomic neuropathy and microangiopathy are the basis for the capillary steal theory and the haemodynamic hypothesis, developed to explain the aetiology of this type of ulcer, in terms of microvascular complications. The aim of the present study was to develop a system to allow assessment of blood flow at prevalent sites of ulceration. Previous studies have been limited to assessment of the bare foot under rest conditions. The new system allows measurements to be made in-shoe, during static and dynamic loading. The system comprises a laser Doppler sensor, a load sensor, measurement shoe, instrumentation and analysis software. The measurement shoe was designed to minimise movement artefact and provide thermal insulation for the foot. A simple flow rig was used to characterise the sensor. The blood flux response was linear (<5% deviation from ideal) for particle concentrations up to 0.25% and for mean particle velocities up to 8mm s(-1). The worst case drift in the response over a six-month period was 3.7%. Device to device repeatability varied by 12.5% over five devices.
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PMID:An in-shoe laser Doppler sensor for assessing plantar blood flow in the diabetic foot. 1155 18

The chronic renal failure patient with diabetes has a lower limb amputation rate 10 times greater than the diabetic population at large. In studies of causal pathways leading to non-traumatic related lower extremity amputation, foot ulcers preceded approximately 84% of the amputations. Even though foot ulcers are more likely to develop in patients with diabetic nephropathy, they are no less likely to heal than are those in diabetic patients with normal renal function. Consequently, attempts to save the diabetic foot even in this high-risk population are justified. The pathogenesis of foot ulceration in the chronic renal failure patient with diabetes is primarily due to peripheral neuropathy. Loss of protective sensation due to sensory neuropathy combined with motor and autonomic neuropathy and macrovascular compromise result in increased risk for foot complications. Evaluation of the foot includes a selective history and a focused examination of skin integrity, presence of sensory neuropathy or vascular insufficiency, and biomechanical and footwear inspection. Effective treatment of diabetic foot complications include appropriate antibiotics (when indicated), meticulous wound care, off-loading, vascular surgery (when indicated), and selective/elective or prophylactic nonvascular surgery. Failure to heal an ulcer can often be traced to common pitfalls, which include: A "cavalier" attitude. W.N.L. exam (We Never Looked). Inadequate off-loading. Failure to establish depth of ulcer and miss "probe to bone." Non-healing means unrelieved pressure and/or no blood. Failure to correct edema. The multidisciplinary diabetic foot clinic model provides an ideal setting for early intervention, treatment, and assistance with preventive strategies.
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PMID:Saving the diabetic foot with special reference to the patient with chronic renal failure. 1157 Jan 48

The purpose of this study was to determine whether peripheral neuropathy explains the apparent association between diabetes and disability in old age, and to evaluate the utility of lower extremity function tests in older diabetic adults with and without neuropathy. We evaluated 39 adults, aged 70-79 years, for pressure sensation (log(10)g), vibration perception threshold (VPT; microns), and electrophysiologic function of the peroneal nerve. The subjects included patients with established diabetic neuropathy (DN; n = 14), diabetic controls without neuropathy (DC; n = 13), and nondiabetic controls (NDC; n = 12). Nonparametric statistical methods were used to relate neuropathy measures to performance in tests of walking speed, static and dynamic balance, coordination, and ankle strength (kilograms). Significant age-adjusted correlations were observed between measures of sensory neuropathy and a variety of performance measures, and electrophysiologic measures were related to static balance. DN subjects had significantly higher pressure sensation than NDC (5.17 vs 3.38g, P < 0.05), higher VPT (62.5 vs 21.7 microm, P < 0.05), and lower peroneal motor response amplitudes at multiple sites. Pressure sensation and nerve conduction measures did not differ between DC and NDC. Compared with NDC, DN subjects performed significantly worse on tests of walking speed (0.99 vs 1.34 m/s; P < 0.05), static balance (4.9 vs 20.4 s; P < 0.05), dynamic balance (9.23 vs 25.52 s; P < 0.05), and coordination (6.73 vs 4.76 s; P < 0.05). No differences were observed in these measures between DC and NDC. Observed differences in physical abilities between older diabetic and nondiabetic adults may have been due to the subset of diabetic individuals with peripheral neuropathy. Quantitative measures of sensory and motor nerve function have distinct effects on physical performance. Interventions aimed at reducing the impact of diabetes-associated disability in old age may have the greatest impact among people with peripheral neuropathy.
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PMID:Diabetes, peripheral neuropathy, and old age disability. 1175 84

Chronic hyperglycemia results in a predominantly sensory neuropathy. Recent studies suggest that dorsal root ganglion (DRG) neurons comprise a specific target and may be responsible for the important complication of diabetic sensory neuropathy, since hyperglycemia for longer than 6 months results in a vacuolar ganglionopathy with associated radiculopathy and distal sensory neuropathy. We undertook morphometric analysis of L5 DRG neurons in seven diabetic rats and six age- and sex-matched littermates. Nerve conduction studies were also performed, and neuropathy was confirmed. Diabetes was induced with streptozotocin; duration of diabetes was 12 months. The DRG count for control rats was 15,304 +/- 991 neurons. Two of seven diabetic DRG counts were reduced, but the group mean count at 14,847 plus minus 1,524 was not significantly reduced. The number of small neurons (type B) considerably exceeded that of large neurons (type A), at a ratio of 71:29. The percentage of large cells was significantly reduced in diabetic compared with control rats (P = 0.01). The large-diameter population can be subdivided into two groups; with this subdivision, the number of neurons < 50 microm was not reduced in samples from diabetic rats, but the neurons of largest size (> or = 50 microm) were significantly reduced (by 41%).
Diabetes 2002 Mar
PMID:Morphometry of dorsal root ganglion in chronic experimental diabetic neuropathy. 1187 86

Recent evidence in both animal models and human sural nerve biopsies indicates an association with oxidative stress, mitochondrial (Mt) membrane depolarization (MMD), and induction of programmed cell death (PCD). In streptozotocin (STZ)-treated diabetic rats, hyperglycemia induces typical apoptotic changes as well as swelling and disruption of the Mt cristae in diabetic dorsal root ganglion neurons (DRG) and Schwann cells (SC), but these changes are only rarely observed in control neurons. In human sural nerve biopsies, from patients with diabetic sensory neuropathy, there is transmission electromicrograph evidence of swelling and disruption of the Mt and cristae compared to patients without peripheral neuropathy. In human SH-SY5Y neurons, rat sensory neurons, and SC, in vivo, there is an increase in reactive oxygen species (ROS) after exposure to 20 mM added glucose. In parallel, there is an initial Mt membrane hyperpolarization followed by depolarization (MMD). In turn, MMD is coupled with cleavage of caspases. Various strategies aimed at inhibiting the oxidative burst, or stabilizing the DeltaPsi(M), block induction of PCD. First, growth factors such as NGF can block induction of ROS and/or stabilize the DeltaPsi(M). This, in turn, is associated with inhibition of PCD. Second, reduction of ROS generation in neuronal Mt prevents neuronal PCD. Third, up-regulation of uncoupling proteins (UCPs), which stabilize the DeltaPsi(M), blocks induction of caspase cleavage. Collectively, these findings indicate that hyperglycemic conditions observed in diabetes mellitus are associated with oxidative stress-induced neuronal and SC death, and targeted therapies aimed at regulating ROS may prove effective in therapy of diabetic neuropathy.
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PMID:Oxidative stress and programmed cell death in diabetic neuropathy. 1197 11

Peripheral neuropathy is a common and debilitating complication of diabetes. In animal models, neurotrophic factors can prevent progression of the neuropathy, but adverse effects prevent systemic administration in adequate doses to treat human disease. We examined whether gene transfer with replication-defective genomic herpes simplex virus (HSV) vectors modified to express nerve growth factor (NGF) could be used to prevent progression of neuropathy in mice. Diabetes induced by streptozotocin (STZ) resulted in a sensory neuropathy manifest by a decrease in the foot sensory nerve amplitude (FSA; control = 20 +/- 0.1 microV, treated = 14 +/- 0.1 microV). Transduction of dorsal root ganglia in vivo with an HSV-based vector expressing NGF under the control of the human cytomegalovirus immediate early promoter (vector SHN) or the HSV latency active promoter 2 (vector SLN) by footpad inoculation 2 weeks after STZ administration protected against the decrease in FSA (22 +/- 1.4 microV and 21 +/- 1.7 microV, respectively) measured 4 weeks later. Injection of SHN into inguinal adipose tissue 2 weeks after onset of diabetes also prevented the decrease in FSA (20 +/- 3.3 microV). These results suggest that gene transfer with an NGF-producing herpes-based vector may prove useful in the treatment of diabetic neuropathy.
Diabetes 2002 Jul
PMID:Herpes simplex-mediated gene transfer of nerve growth factor protects against peripheral neuropathy in streptozotocin-induced diabetes in the mouse. 1208 54

The effect of capsaicin (0.1 microM) on heart rate and coronary flow was studied in Langendorff-perfused heart from streptozotocin-induced (50 mg/kg i.v.) diabetic rats where sensory neuropathy developed. In hearts from animals 4- and 8-week diabetes baseline heart rate and coronary flow decreased from 317.9 +/- 2.9 b.p.m. and 13.4 +/- 0.7 m/min to 255.1 +/- 12.7 and 219.8 +/- 2.8 b.p.m. and 8.9 +/- 0.6 and 10.0 +/- 0.1 ml/min (P<0.05), respectively. Capsaicin significantly decreased both variables in either normal or 4-week diabetic animals its effects, however, on coronary flow or heart rate were missing in preparations from 8-week diabetic rats. Endothelin-1 (0.1 nM), the putative mediator of the capsaicin effect, significantly decreased heart rate and coronary flow irrespective of the presence or absence of diabetes. In the femoral nerve of streptozotocin-treated animals conduction velocity involving both fast conducting A- and slow-conducting C-fibres was decreased proportional to the duration of the pre-existing diabetic state. It is concluded that in insulin deficient diabetes the diminished responses evoked by capsaicin on heart rate and coronary flow are signs of sensory neuropathy. This is related to a feeble endothelin release from sensory nerve endings without changes in post-receptor mechanisms mediating the endothelin effects.
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PMID:Impaired capsaicin-induced decrease in heart rate and coronary flow in isolated heart of diabetic rats. 1216 79


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